Effects of Indole-3-Lactic Acid, a Metabolite of Tryptophan, on IL-4 and IL-13-Induced Human Skin-Equivalent Atopic Dermatitis Models

Abstract

Indole-3-lactic acid (I3LA) is a well-known metabolite involved in tryptophan metabolism. Indole derivatives are involved in the differentiation of immune cells and the synthesis of cytokines via the aryl hydrocarbon receptors for modulating immunity, and the indole derivatives may be involved in allergic responses. I3LA was selected as a candidate substance for the treatment of atopic dermatitis (AD), and its inhibitory effect on AD progression was investigated. Full-thickness human skin equivalents (HSEs) consisting of human-derived cells were generated on microfluidic chips and stimulated with major AD-inducing factors. The induced AD-HSEs were treated with I3LA for 7 days, and this affected the AD-associated genetic biomarkers and increased the expression of the major constituent proteins of the skin barrier. After the treatment for 14 days, the surface became rough and sloughed off, and there was no significant difference between the increased AD-related mRNA expression and the skin barrier protein expression. Therefore, the short-term use of I3LA for approximately one week is considered to be effective in suppressing AD.

Induction of psoriasis- and atopic dermatitis-like phenotypes in 3D skin equivalents with a fibroblast-derived matrix

“…The Ps-associated cytokines IL-17A and IL-22 have already been shown to directly downregulate the FLG , LOR and CK10 gene expression 51 , 52 . Suppression of FLG and LOR gene expression was also observed upon AD-related IL-13 and IL-4 stimulation in other studies 10 , 53 . Our in vitro models confirm these findings.…”

“…Our in vitro models confirm these findings. A reduction of IVL protein levels was reported for AD skin and in vitro experiments evidenced diminished IVL mRNA levels of human keratinocytes in presence of IL-4 and/or IL-13 50 , 53 . Interestingly, despite potently declined IVL mRNA levels, the protein expression was barely affected in our Ps skin equivalents.…”

A cross talk between microbial metabolites and host immunity: Its relevance for allergic diseases

“…Several bacteria were described to metabolize diet‐derived L‐tryptophan; Escherichia coli can convert dietary tryptophan to indole, 39 Clostridium sporogenes produce tryptamine 40 and Lactobacilli produce indole derivatives 39 . Indole derivatives can modulate the immune response through the AHR receptor, 41 influencing Th cell differentiation and cytokine synthesis towards an anti‐inflammatory state 42 . Additionally, L‐tryptophan derivatives can directly modulate macrophage activation, while treatment with indole‐3‐butyric acid (IBA) and indole‐3‐lactic acid (ILA) was shown to suppress LPS‐induced cytokine production in vitro 43 …”

Recent advances in understanding the role of the skin microbiome in the treatment of atopic dermatitis

“…Postbiotics have the advantage of being able to mimic the same benefits as probiotics. This strategy shows how some representative metabolites of postbiotics and tryptophan metabolites, such as IAId, work to improve the skin barrier 35,103,104 . (B) Phage therapy involves the lysis of microbes by phages, such as SaGU1, that can specifically remove S. aureus .…”

“…IAId suppresses MC903‐induced AD‐like dermatitis by inhibiting Thymic stromal lymphopoietin (TSLP) expression in keratinocytes via an AhR‐dependent mechanism 35 . In addition, some effects of indole‐3‐lactic acid have been reported in Th2 cytokine IL‐4‐ and IL‐13‐induced AD in the human skin equivalent (HSE) model 104 …”